Novel oxime derivatives and their use as allosteric modulators of metabotropic glutamate receptors   

Abstract: The present invention provides new oxime derivatives of the general formula (I), pharmaceutical compositions containing them and their use for the treatment and/or prophylaxis of conditions associated with altered glutamatergic signalling and/or functions, and/or conditions which can be affected by alteration of glutamate level or signalling in mammals. This invention further provides new oxime derivatives of the general formula (I) consisting of modulators of nervous system receptors sensitive to glutamate, which makes them particularly suitable for the treatment and/or prophylaxis of acute and chronic neurological and/or psychiatric disorders. In particular embodiments, the new oxime derivatives of the invention are modulators of metabotropic glutamate receptors (mGluRs). The invention further provides positive allosteric modulators of mGluRs and more specifically positive alSosteric modulators of mGluR4.

The present invention provides new oxime derivatives of the general formula (I), pharmaceutical compositions containing them and their use for the treatment and/or prophylaxis of conditions associated with altered glutamatergic signalling and/or functions, and/or conditions which can be affected by alteration of glutamate level or signalling in mammals. This invention further provides new oxime derivatives of the general formula (I) consisting of modulators of nervous system receptors sensitive to glutamate, which makes them particularly suitable for the treatment and/or prophylaxis of acute and chronic neurological and/or psychiatric disorders. In particular embodiments, the new oxime derivatives of the invention are modulators of metabotropic glutamate receptors (mGluRs). The invention further provides positive allosteric modulators of mGluRs and more specifically positive allosteric modulators of mGluR4.

Glutamatergic pathways have been shown to be clearly involved in the physiopathology of a number of neuronal damages and injuries. Many nervous system disorders including epilepsy and chronic or acute degenerative processes such as for example Alzheimer\'s disease, Huntington\'s disease, Parkinson\'s disease and amyotrophic lateral sclerosis (Mattson M P., Neuromolecular Med., 3(2), 65-94, 2003), but also AIDS-induced dementia, multiple sclerosis, spinal muscular atrophy, retinopathy, stroke, ischemic, hypoxia, hypoglycaemia and various traumatic brain injuries, involve neuronal cell death caused by imbalanced levels of glutamate. It has also been shown that drug-induced neurotoxicity, for example neurotoxic effects of methamphetamine (METH) on striatal dopaminergic neurons, could actually be mediated by over-stimulation of the glutamate receptors (Stephans S E and Yamamoto B K, Synapse 17(3), 203-9, 1994). Antidepressant and anxiolytic-like effects of compounds acting on glutamate have also been observed on mice, suggesting that glutamatergic transmission is implicated in the pathophysiology of affective disorders such as major depression, schizophrenia and anxiety (Palucha A et al., Pharmacol. Ther. 115(1), 116-47, 2007; Cryan J F at al., Eur. J. Neurosc. 17(11), 2409-17, 2003; Conn P J at al., Trends Pharmacol. Sci. 30(1), 25-31, 2009). Consequently, any compound able to modulate glutamatergic signalling or function would constitute a promising therapeutic compound for many disorders of the nervous system.

Moreover, compounds modulating glutamate level or signalling may be of great therapeutic value for diseases and/or disorders not directly mediated by glutamate levels and/or glutamate receptors malfunctioning, but which could be affected by alteration of glutamate levels or signaling.

In the central nervous system (CNS), L-glutamate (Glu) is the main excitatory neurotransmitter and is referred to as an excitatory amino-acid (EAA), and gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter. The balance between excitation and inhibition is of utmost importance to CNS functions, and dysfunctions of either of the two can be related to various neurological disorders.

Glutamate is ubiquitously distributed in the nervous system in high concentrations, especially in the brain and spinal cord of mammals, where it is working at a variety of excitatory synapses being thereby involved in virtually all physiological functions such as motor control, vision, central control of heart, processes of learning and memory. However, a large number of studies have established that cellular communication involving glutamate can also lead to a mechanism of cell destruction. This combination of neuroexcitatory activities and neurotoxic properties is called excitotoxicity.

Glutamate operates through two classes of receptors (Bräuner-Osborne H at al., J. Med. Chem. 43(14), 2609-45, 2000). The first class of glutamate receptors is directly coupled to the opening of cation channels in the cellular membrane of the neurons. Therefore they are called ionotropic glutamate receptors (IGluRs). The IGluRs are divided in three subtypes, which are named according to the depolarizing action of their selective agonists: N-methyl-D-aspartate (NMDA), α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), and kainic acid (KA). The second class of glutamate receptor consists of G-protein coupled receptors (GPCRs) called metabotropic glutamate receptors (mGluRs). These mGluRs are localized both pre- and post-synaptically. They are coupled to multiple second messenger systems and their role is to regulate the activity of the ionic channels or enzymes producing second messengers via G-proteins binding the GTP (Conn P J and Pin J P., Annu. Rev. Pharmacol. Toxicol., 37, 205-37, 1997). Although they are generally not directly involved in rapid synaptic transmission, the mGluRs modulate the efficacy of the synapses by regulating either the post-synaptic channels and their receptors, or the pre-synaptic release or recapture of glutamate. Therefore, mGluRs play an important role in a variety of physiological processes such as long-term potentiation and long-term depression of synaptic transmission, regulation of baroreceptive reflexes, spatial learning, motor learning, and postural and kinetic integration.

To date, eight mGluRs have been cloned and classified in three groups according to their sequence homologies, pharmacological properties and signal transduction mechanisms. Group I is constituted of mGluR1 and mGluR5, group II of mGluR2 and mGluR3 and group III of mGluR4, mGluR6, mGluR7 and mGluR8 (Pin J P and Acher F., Curr. Drug Targets CNS Neurol. Disord., 1(3), 297-317, 2002; Schoepp D D at al., Neuropharmacology, 38(10), 1431-76, 1999).

mGluRs modulators can be classified in two families depending on their site of interaction with the receptor (see Bräuner-Osborne H et al., J. Med. Chem. 43(14), 2609-45, 2000 for review). The first family consists in orthosteric modulators (or competitive modulators) able to interact with the glutamate binding-site of the mGluRs, which is localized in the large extra-cellular N-terminal part of the receptor (about 560 amino acids). Therefore, they are glutamate analogs and constitute a highly polar family of ligand. Examples of orthosteric modulators are S-DHPG or LY-367385 for group I mGluRs, LY-354740 or (2R-4R)-APDC for group II mGluRs and ACPT-I or L-AP4 for group III mGluRs. The second family of mGluRs modulators consists in allosteric modulators that interact with a different site from the extracellular active site of the receptor (see Bridges T M et al., ACS Chem Biol, 3(9), 530-41, 2008 for review). Their action results in a modulation of the effects induced by the endogenous ligand glutamate. Examples of such allosteric modulators are Ro-674853, MPEP or JNJ16259685 for group I mGluRs and CBiPES, LY181837 or LY487379 for group II mGluRs.

For groups III mGluRs, examples of allosteric modulators were so far described for the mGluR subtype 4 (mGluR4). PHCCC, MPEP and SIB1893 (Maj M at al., Neuropharmacology, 45(7), 895-903, 2003; Mathiesen J M at al., Br. J. Pharmacol. 138(6), 1026-30, 2003) were the first ones described in 2003. More recently, more potent positive allosteric modulators were reported in the literature (Niswender C M et al., Mol. Pharmacol. 74(5), 1345-58, 2008; Niswender C M at al., Bioorg. Med. Chem. Lett, 18(20), 5626-30, 2008; Williams R et al., Bioorg. Med. Chem. Lett. 19(3), 962-6, 2009; Engers D W et al., J. Med. Chem. May 27, 2009) and in two patent publications describing families of amido and heteroaromatic compounds (WO 2009/010454 and WO 2009/010455).

Numerous studies have already described the potential applications of mGluR modulators in neuroprotection (see Bruno V et al., J. Cereb. Blood Flow Metab., 21(9), 1013-33, 2001 for review). For instance, antagonist compounds of group I mGluRs showed interesting results in animal models for anxiety and postischemic neuronal injury (Pilc A et al., Neuropharmacology, 43(2), 181-7, 2002; Meli E et al., Pharmacol. Biochem. Behav., 73(2), 439-46, 2002), agonists of group II mGluRs showed good results in animal models for Parkinson and anxiety (Konieczny J et al., Naunyn-Schmiederbergs Arch. Pharmacol., 358(4), 500-2, 1998).

Group III mGluR modulators showed positive results in several animal models of schizophrenia (Palucha-Poniewiera A et al., Neuropharmacology, 55(4), 517-24, 2008) and chronic pain (Goudet C et al., Pain, 137(1), 112-24, 2008; Zhang H M et al., Neuroscience, 158(2), 875-84, 2009).

Group III mGluR were also shown to exert the excitotoxic actions of homocysteine and homocysteic acid contributing to the neuronal pathology and immunosenescence that occur in Alzheimer Disease (Boldyrev A A and Johnson P, J. Alzheimers Dis. 11(2), 219-28, 2007).

Moreover, group III mGluR modulators showed promising results in animal models of Parkinson and neurodegeneration (Conn P J et al., Nat. Rev. Neuroscience, 6(10), 787-98, 2005 for review; Vernon A C et al., J. Pharmacol. Exp. Ther., 320(1), 397-409, 2007; Lopez S et al., Neuropharmacology, 55(4), 483-90, 2008; Vernon A C et al, Neuroreport, 19(4), 475-8, 2008). It was further demonstrated with selective ligands that the mGluR subtype implicated in these antiparkinsonian and neuroprotective effects was mGluR4 (Marino M J et al., Proc. Natl. Acad. Sci. USA 100(23), 13668-73, 2003; Battaglia G et al., J. Neurosci. 26(27), 7222-9, 2006; Niswender C M et al., Mol. Pharmacol. 74(5), 1345-58, 2008).

mGluR4 modulators were also shown to exert anxiolytic activity (Stachowicz K et al., Eur. J. Pharmacol., 498(1-3), 153-6, 2004) and anti-depressive actions (Palucha A et al., Neuropharmacology 46(2), 151-9, 2004; Klak K et al., Amino Acids 32(2), 169-72, 2006).

In addition, mGluR4 were also shown to be involved in glucagon secretion inhibition (Uehara S., Diabetes 53(4), 998-1006, 2004). Therefore, orthosteric or positive allosteric modulators of mGluR4 have potential for the treatment of type 2 diabetes through its hypoglycemic effect.

Moreover, mGluR4 was shown to be expressed in prostate cancer cell-line (Pessimissis N et al., Anticancer Res. 29(1), 371-7, 2009) or colorectal carcinoma (Chang H J et al., Cli. Cancer Res. 11(9), 3288-95, 2005) and its activation with PHCCC was shown to inhibit growth of medulloblastomas (Iacovelli L et al., J. Neurosci. 26(32) 8388-97, 2006), mGluR4 modulators may therefore have also potential role for the treatment of cancers.

Finally, receptors of the umami taste expressed in taste tissues were shown to be variants of the mGluR4 receptor (Eschle B K., Neuroscience, 155(2), 522-9, 2008). As a consequence, mGluR4 modulators may also be useful as taste agents, flavour agents, flavour enhancing agents or food additives.

Chromone-derived core structures for pharmaceutically active compounds were described in the patent application WO 2004/092154. In the latter application, they are disclosed as inhibitors of protein kinases.

EP-A-0 787 723 relates to specific cyclopropachromencarboxylic acid derivatives which are said to have mGluR antagonistic activity.

The present invention relates to compounds of the general formula (I):

and pharmaceutically acceptable salts, solvates and prodrugs thereof.

R1, R2, R3, and R4 each independently represent a -L-R group.

L represents a bond, a C1-C10 alkylene, a C2-C10 alkenylene, or a C2-C10 alkynylene, wherein said alkylene, said alkenylene or said alkynylene is optionally substituted with one or more groups independently selected from halogen, —CF3, —CN, —OH, or —NH2, and further wherein one or more —CH2— units comprised in said alkylene, said alkenylene or said alkynylene are each optionally replaced by a group independently selected from —O—, —NR11—, —CO—, —S—, —SO—, or —SO2—.

R is selected from hydrogen, C1-C10 alkyl, halogen, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, —NR11R12, —OR11, —SR11, —SOR11, —SO2R11, —CF3, or —CN, wherein said optionally substituted aryl, said optionally substituted heteroaryl, said optionally substituted cycloalkyl, or said optionally substituted heterocycloalkyl may be substituted with one or more groups independently selected from C1-C4 alkyl, halogen, —CF3, —CN, —OH, —O(C1-C4 alkyl), —NH2, —NH(C1-C4 alkyl), —N(C1-C4 alkyl)(C1-C4 alkyl) wherein the two C1-C4 alkyl moieties of said —N(C1-C4 alkyl)(C1-C4 alkyl) are optionally mutually linked to form a ring together with the nitrogen atom which they are attached to, or -L1-R13.

R11 and R12 are each independently selected from hydrogen, optionally substituted C1-C10 alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, or —CF3, wherein said optionally substituted alkyl, said optionally substituted aryl, said optionally substituted heteroaryl, said optionally substituted cycloalkyl, or said optionally substituted heterocycloalkyl may be substituted with one or more groups independently selected from C1-C4 alkyl, halogen, —CF3, —CN, —OH, —O(C1-C4 alkyl), —NH2, —NH(C1-C4 alkyl), or —N(C1-C4 alkyl)(C1-C4 alkyl), wherein the two C1-C4 alkyl moieties of said —N(C1-C4 alkyl)(C1-C4 alkyl) are optionally mutually linked to form a ring together with the nitrogen atom which they are attached to.

L1 is selected from a bond, C1-C10 alkylene, C2-C10 alkenylene, or C2-C10 alkynylene, wherein one or two —CH2— units comprised in said alkylene, said alkenylene or said alkynylene are each optionally replaced by a group independently selected from —O—, —NH—, —N(C1-C4 alkyl)-, —CO—, —S—, —SO— or —SO2—.

R13 is selected from hydrogen, C1-C4 alkyl, halogen, optionally substituted phenyl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, —NH2, —NH(C1-C4 alkyl), —N(C1-C4 alkyl)(C1-C4 alkyl), —OH, —O(C1-C4 alkyl), —SH, —S(C1-C4 alkyl), —CF3, or —CN, wherein said optionally substituted phenyl, said optionally substituted heteroaryl, said optionally substituted cycloalkyl, or said optionally substituted heterocycloalkyl may be substituted with one or more groups independently selected from C1-C4 alkyl, halogen, —CF3, —CN, —OH, —O(C1-C4 alkyl), —NH2, —NH(C1-C4 alkyl), or —N(C1-C4 alkyl)(C1-C4 alkyl), wherein the two C1-C4 alkyl moieties of said —N(C1-C4 alkyl)(C1-C4 alkyl) are optionally mutually linked to form a ring together with the nitrogen atom which they are attached to.

R5 is selected from hydrogen, C1-C4 alkyl, halogen, —CF3, —CN, —OH, —O(C1-C4 alkyl), —COOH, —COO(C1-C4 alkyl), —CONH2, —CONH(C1-C4 alkyl), —CON(C1-C4 alkyl)(C1-C4 alkyl), wherein the two C1-C4 alkyl moieties of said —CON(C1-C4 alkyl)(C1-C4 alkyl) are optionally mutually linked to form a ring together with the nitrogen atom which they are attached to, —NH2, —NH(C1-C4 alkyl), or —N(C1-C4 alkyl)(C1-C4 alkyl), wherein the two C1-C4 alkyl moieties of said —N(C1-C4 alkyl)(C1-C4 alkyl) are optionally mutually linked to form a ring together with the nitrogen atom which they are attached to.

A is a bicyclic moiety corresponding to formula (II):

which may be saturated or unsaturated, and wherein: n is 0 or 1; X1 to X6 are each independently selected from N,N(Rx1), C(Rx2), C(Rx2)(Rx3), O, S, S(O), S(O)2, or C(O); X7 is N or N(Rx1); any of groups X1 to X7 containing a nitrogen atom may form an N-oxide group; X8 and X9 are each independently selected from N, C, or C(Rx2); each Rx1 is independently selected from hydrogen, C1-C4 alkyl, —OH, —O(C1-C4 alkyl), or —(C1-C4 alkylene)-phenyl; and each Rx2 and each Rx3 is independently selected from hydrogen, C1-C4 alkyl, halogen, —CF3, —CN, —OH, —O(C1-C4 alkyl), —COOK, —COO(C1-C4 alkyl), —CONH2, —CONH(C1-C4 alkyl), —CON(C1-C4 alkyl)(C1-C4 alkyl), —NH2, —NH(C1-C4 alkyl), or —N(C1-C4 alkyl)(C1-C4 alkyl), wherein the two C1-C4 alkyl moieties of said —N(C1-C4 alkyl)(C1-C4 alkyl) or of said —CON(C1-C4 alkyl)(C1-C4 alkyl) are optionally mutually linked to form a ring together with the nitrogen atom which they are attached to.

In this description, the bicyclic ring system of formula (I) including the O-heteroatom and the oxime group, to which the substituents R1 to R5 and A are attached, is also referred to as “chromone moiety”.

Thus, the present invention relates to new oxime derivatives of the general formula (I) as described and defined herein and pharmaceutically acceptable salts, solvates and prodrugs thereof, pharmaceutical compositions containing any of the aforementioned entities and their use for the treatment and/or prophylaxis of conditions associated with altered glutamatergic signalling and/or functions, and/or conditions which can be affected by alteration of glutamate level or signalling in mammals. It further relates to a method of treating and/or preventing conditions associated with altered glutamatergic signalling and/or functions, and/or conditions which can be affected by alteration of glutamate level or signalling in a mammal. Accordingly, the present invention provides a method of treating and/or preventing a disease or disorder, in particular a condition associated with altered glutamatergic signalling and/or functions, and/or a condition which can be affected by alteration of glutamate level or signalling, the method comprising the administration of a compound of the general formula (I) as described and defined herein, or a pharmaceutically acceptable salt, solvate or prodrug thereof, or a pharmaceutical composition comprising any of the aforementioned entities, to a subject (preferably, a mammal; more preferably, a human) in need of such treatment or prevention. In further embodiments the compounds of the general formula (I) are modulators of mGluRs of the nervous system. In preferred embodiments the compounds of the invention are allosteric modulators of the mGluRs and in a most preferred embodiment they are positive allosteric modulators of mGluR4.

The conditions associated with altered glutamatergic signalling and/or functions, and/or conditions which can be affected by alteration of glutamate level or signalling, and which can be treated and/or prevented with the compounds or the pharmaceutical compositions according to the invention, include in particular: epilepsy, including newborn, infantile, childhood and adult syndromes, partial (localization-related) and generalized epilepsies, with partial and generalized, convulsive and non-convulsive seizures, with and without impairment of consciousness, and status epilepticus; Dementias and related diseases, including dementias of the Alzheimer\'s type (DAT), Alzheimer\'s disease, Pick\'s disease, vascular dementias, Lewy-body disease, dementias due to metabolic, toxic and deficiency diseases (including alcoholism, hypothyroidism, and vitamin B12 deficiency), AIDS-dementia complex, Creutzfeld-Jacob disease and atypical subacute spongiform encephalopathy; Parkinsonism and movement disorders, including Parkinson\'s disease, multiple system atrophy, progressive supranuclear palsy, corticobasal degeneration, hepatolenticular degeneration, chorea (including Huntington\'s disease and hemiballismus), athetosis, dystonias (including spasmodic torticollis, occupational movement disorder, Gilles de la Tourette syndrome), tardive or drug induced dyskinesias, tremor and myoclonus; Motor neuron disease or amyotrophic lateral sclerosis (ALS); Other neurodegenerative and/or hereditary disorders of the nervous system, including spinocerebrellar degenerations such as Friedrich\'s ataxia and other hereditary cerebellar ataxias, predominantly spinal muscular atrophies, hereditary neuropathies, and phakomatoses; Disorders of the peripheral nervous system, including trigeminal neuralgia, facial nerve disorders, disorders of the other cranial nerves, nerve root and plexus disorders, mononeuritis such as carpal tunnel syndrome and sciatica, hereditary and idiopathic peripheral neuropathies, inflammatory and toxic neuropathies; Multiple sclerosis and other demyelinating diseases of the nervous system; Infantile cerebral palsy (spastic), monoplegic, paraplegic or tetraplegic; Hemiplegia and hemiparesis, flaccid or spastic, and other paralytic syndromes; Cerebrovascular disorders, including subarachnoid hemorrhage, intracerebral hemorrhage, occlusion and stenosis of precerebral arteries, occlusion of cerebral arteries including thrombosis and embolism, brain ischemia, stroke, transient ischemic attacks, atherosclerosis, cerebrovascular dementias, aneurysms, cerebral deficits due to cardiac bypass surgery and grafting; Migraine, including classical migraine and variants such as cluster headache; Headache; Myoneural disorders including myasthenia gravis, acute muscle spasms, myopathies including muscular dystrophies, mytotonias and familial periodic paralysis; Disorders of the eye and visual pathways, including retinal disorders, and visual disturbances; Intracranial trauma/injury and their sequels; Trauma/injury to nerves and spinal cord and their sequels; Poisoning and toxic effects of nonmedicinal substances; Accidental poisoning by drugs, medicinal substances and biologicals acting on the central, peripheral and autonomic system; Neurological and psychiatric adverse effects of drugs, medicinal and biological substances; Disturbance of sphincter control and sexual function; Mental disorders usually diagnosed in infancy, childhood or adolescence, including: mental retardation, learning disorders, motor skill disorders, communication disorders, pervasive developmental disorders, attention deficit and disruptive behaviour disorders, feeding and eating disorders, TIC disorders, elimination disorders; Delirium and other cognitive disorders; Substance related disorders including: alcohol-related disorders, nicotine-related disorders, disorders related to cocaine, opioids, cannabis, hallucinogens and other drugs; Schizophrenia and other psychotic disorders; Mood disorders, including depressive disorders and bipolar disorders; Anxiety disorders, including panic disorders, phobias, obsessive-compulsive disorders, stress disorders, generalized anxiety disorders; Eating disorders, including anorexia and bulimia; Sleep disorders, including dyssomnias (insomnia, hypersomnia, narcolepsy, breathing related sleep disorder) and parasomnias; Medication-induced movement disorders (including neuroleptic-induced parkinsonism and tardive dyskinesia); Endocrine and metabolic diseases including diabetes, disorders of the endocrine glands, hypoglycaemia; Acute and chronic pain; Nausea and vomiting; Irritable bowel syndrome; or cancers.

In particular, the conditions associated with altered glutamatergic signalling and/or functions, and/or conditions which can be affected by alteration of glutamate level or signalling to be treated and/or prevented by the compounds or the pharmaceutical compositions according to the invention, include: Dementias and related diseases, including dementias of the Alzheimer\'s type (DAT), Alzheimer\'s disease, Pick\'s disease, vascular dementias, Lewy-body disease, dementias due to metabolic, toxic and deficiency diseases (including alcoholism, hypothyroidism, and vitamin B12 deficiency), AIDS-dementia complex, Creutzfeld-Jacob disease and atypical subacute spongiform encephalopathy; Parkinsonism and movement disorders, including Parkinson\'s disease, multiple system atrophy, progressive supranuclear palsy, corticobasal degeneration, hepatolenticular degeneration, chorea (including Huntington\'s disease and hemiballismus), athetosis, dystonias (including spasmodic torticollis, occupational movement disorder, Gilles de la Tourette syndrome), tardive or drug induced dyskinesias, tremor and myoclonus; Acute and chronic pain; Anxiety disorders, including panic disorders, phobias, obsessive-compulsive disorders, stress disorders and generalized anxiety disorders; Schizophrenia and other psychotic disorders; Mood disorders, including depressive disorders and bipolar disorders; Endocrine and metabolic diseases including diabetes, disorders of the endocrine glands and hypoglycaemia; or cancers.

The present invention further provides a method for identifying an agent that binds to metabotropic glutamate receptor 4 (mGluR4), or in other words for determining the capability of one or more test agent(s) to bind to the receptor, comprising the following steps: (a) contacting mGluR4 with a compound of the present invention which is labeled, preferably radio-Labeled or fluorescence-labeled, under conditions that permit binding of the compound to mGluR4, thereby generating a bound, labeled compound; (b) detecting a signal that corresponds to the amount of the bound, labeled compound in the absence of test agent; (c) contacting the bound, labeled compound with a test agent; (d) detecting a signal that corresponds to the amount of the bound labeled compound in the presence of test agent; and (e) comparing the signal detected in step (d) to the signal detected in step (b) to determine whether the test agent binds to mGluR4. As will be understood, a substantially unchanged signal detected in step (d) in comparison with the signal detected in step (b) indicates that the test agent does not bind to the receptor, or binds to the receptor less strongly than the compounds according to the invention. A decreased or increased signal detected in step (d) in comparison with the signal detected in step (b) indicates that the test agent binds to the receptor. Thus, agents that bind to mGluR4 can be identified among the test agents employed in the above method. It will further be understood that it is preferred to remove unbound labeled compounds, e.g. in a washing step, before carrying out steps (b) and (d).

The mGluR4 which is used in the above method may be a human form (Flor P J, Lukic S, Rüegg D, Leonhardt T, Knöpfel T, Kuhn R. 1995. Neuropharmacology. 34:149-155. Makoff A, Lelchuk R, Oxer M, Harrington K, Emson P. 1996. Brain Res. Mol. Brain. Res. 37:239-248. Wu 5, Wright R A, Rockey P K, Burgett S G, Arnold J S, Rosteck P R Jr, Johnson B G, Schoepp D D, Belagaje R M. 1998. Brain Res. Mot. Brain Res. 53:88-97.), e.g. a protein of the accession number NP—000832 or a protein having at least 80% (preferably, at least 90%; more preferably, at least 95%; even more preferably, at least 99%) amino acid identity to said protein of the accession number NP—000832, or a non-human form, including e.g. a mouse form or rat form (Tanabe Y, Masu M, Ishii T, Shigemoto R, Nakanishi S. 1992. Neuron. 8:169-179.), or a homolog thereof found in a different species (e.g. in a different mammalian species), or a mutein of any of the aforementioned entitites which mutein retains the mGluR4 activity. Said mutain can preferably be obtained by substitution, insertion, addition and/or deletion of one or more (such as, e.g., 1 to 20, including 1 to 10 or 1 to 3) amino acid residues of said aforementioned entitites. The mGluR4 used in the above method may also be a functional fragment of any of the aforementioned entitites (including said muteins), i.e. a fragment which retains the mGluR4 activity of the respective aforementioned entity or, in other words, a fragment having essentially the same biological activity (i.e., at least about 60% activity, preferably at least about 70% activity, more preferably at least about 80% activity, even more preferably at least about 90% activity) as the respective aforementioned entity. A person skilled in the art is readily in a position to determine whether mGluR4 activity is retained using techniques known in the art, e.g. knock-out and rescue experiments. Furthermore, the mGluR4 used in the above method may also be a compound comprising any one or more of the aforementioned entitites (including, without limitation, a protein of the accession number NP—000832, a protein having at least 80% amino acid identity to said protein of the accession number NP—000832, or a functional fragment thereof), wherein the mGluR4 activity is retained. Preferably, the mGluR4 used in the above method is a human form.

The compounds of the general formula (I) will be described in more detail in the following:

R1, R2, R3, and R4 each independently represent a -L-R group.

L represents a bond, C1-C10 alkylene, C2-C10 alkenylene, or C2-C10 alkynylene. Said alkylene, said alkenylene or said alkynylene is optionally substituted with one or more (such as, e.g., one, two, three, or four) groups independently selected from halogen, —CF3, —CN, —OH, or —NH2.

Moreover, one or more (such as, e.g., one, two, three, or four), preferably one or two, more preferably one, —CH2— units comprised in said alkylene, said alkenylene or said alkynylene are each optionally replaced by a group independently selected from: —O—, —NR11—, —CO—, —S—, —SO—, or —SO2—. This includes the option that the replacing groups —NR11— and —CO— are combined, in any order, to form an amide group. Otherwise, if more than one —CH2— unit is replaced, it is preferred that these —CH2— units are non-adjacent. Preferably, no —CH2— unit, one —CH2— unit or two —CH2— units are each replaced by a group independently selected from —O—, —NR11—, —CO—, or —S—. More preferably, no —CH2— unit is replaced or one —CH2— unit or two —CH2— units are each replaced by a group independently selected from —O—, —NR11—, or —S—. Even more preferably, no —CH2— unit is replaced or one or two —CH2— units are each replaced by —O—.

More preferably, L is a bond, C1-C6 alkylene, C2-C6 alkenylene, or C2-C6 alkynylene, wherein one or two —CH2— units comprised in said alkylene, said alkenylene or said alkynylene are each optionally replaced by a group independently selected from —O—, —NR11—, —CO—, or —S—.

Even more preferably, L is a bond, C1-C6 alkylene, C2-C6 alkenylene, or C2-C6 alkynylene, wherein one or two —CH2— units comprised in said alkylene, said alkenylene, or said alkynylene are each optionally replaced by —O—.

Most preferably, L is a bond or C1-C6 alkylene, wherein one or two —CH2— units comprised in said alkylene are each optionally replaced by —O—.

R is selected from hydrogen, C1-C10 alkyl, halogen, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, —NR11R12, —OR11, —SR11, —SOR11, —SO2R11, —CF3, or —CN, wherein said optionally substituted aryl, said optionally substituted heteroaryl, said optionally substituted cycloalkyl, or said optionally substituted heterocycloalkyl may be substituted with one or more (such as, e.g., one, two, three, or four), preferably one or two, substituent groups independently selected from C1-C4 alkyl, halogen, —CF3, —CN, —OH, —O(C1-C4 alkyl), —NH2, —NH(C1-C4 alkyl), —N(C1-C4 alkyl)(C1-C4 alkyl) wherein the two C1-C4 alkyl moieties of said —N(C1-C4 alkyl)(C1-C4 alkyl) are optionally mutually linked to form a ring (such as, e.g., a pyrrolidinyl ring or a piperidinyl ring) together with the nitrogen atom which they are attached to, or -L-R13. Said substituent groups are preferably selected from C1-C4 alkyl, —(C1-C4 alkylene)-OH, alkylene)-O—(C1-C4 alkyl), —OH, —O(C1-C4 alkyl), —O—(C1-C4 alkylene)-O—(C1-C4 alkyl), —NH2, —NH(C1-C4 alkyl), —N(C1-C4 alkyl)(C1-C4 alkyl) wherein the two C1-C4 alkyl moieties of said —N(C1-C4 alkyl)(C1-C4 alkyl) are optionally mutually linked to form a ring together with the nitrogen atom which they are attached to, —CF3, or halogen, and more preferably selected from C1-C4 alkyl, —(C1-C4 alkylene)-OH, —(C1-C4 alkylene)-O—(C1-C4 alkyl), —O(C1-C4 alkyl), —N(C1-C4 alkyl)(C1-C4 alkyl) wherein the two C1-C4 alkyl moieties of said —N(C1-C4 alkyl)(C1-C4 alkyl) are optionally mutually linked to form a ring together with the nitrogen atom which they are attached to, or halogen, Said halogen may, for example, be selected from fluoro, chloro, bromo, or iodo.

Preferably, R is selected from: hydrogen; optionally substituted aryl; optionally substituted heteroaryl having 5 or 6 ring atoms, wherein 1, 2, or 3 ring atoms are each independently selected from O, S, or N and the other ring atoms are carbon atoms; optionally substituted heterocycloalkyl having 3 to 10 ring atoms, wherein one or more (such as, e.g., one, two, or three) ring atoms are each independently selected from O, S, or N and the other ring atoms are carbon atoms; —NH(C1-C4 alkyl); —N(C1-C4 alkyl)(C1-C4 alkyl); or —O(C1-C4 alkyl), Said aryl may, for example, be a phenyl. Said heteroaryl may, for example, be selected from pyridinyl, thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, isoxazolyl, or furazanyl. Said heterocycloalkyl may, for example, be selected from tetrahydrofuranyl, piperidinyl, piperazinyl, pyrrolidinyl, imidazolidinyl, morpholinyl, pyrazolidinyl, tetrahydrothienyl, oxazolidinyl, isoxazolidinyl, aziridinyl, azetidinyl, octahydroquinolinyl, octahydroisoquinolinyl, azepanyl, diazepanyl, oxazepanyl or 2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl.

More preferably, R is selected from: hydrogen; optionally substituted phenyl; optionally substituted heteroaryl having 5 or 6 ring atoms, wherein 1, 2, or 3 ring atoms are each independently selected from O, S, or N and the other ring atoms are carbon atoms; —O(C1-C4 alkyl); or optionally substituted heterocycloalkyl having 3 to 10 ring atoms, wherein one or more ring atoms are each independently selected from O, S, or N and the other ring atoms are carbon atoms.

Even more preferably, R is selected from: hydrogen; optionally substituted phenyl; optionally substituted heteroaryl having 5 or 6 ring atoms, wherein 1, 2, or 3 ring atoms are each independently selected from O, S, or N and the other ring atoms are carbon atoms; or optionally substituted heterocycloalkyl having 5 to 7 ring atoms, wherein one or two ring atoms are each independently selected from N or O and the other ring atoms are carbon atoms.

As is apparent from the above, preferred combinations -L-R are those wherein L is a bond, C1-C6 alkylene, C2-C6 alkenylene, or C2-C6 alkynylene, wherein one or two —CH2— units comprised in said alkylene, said alkenylene, or said alkynylene are each optionally replaced by —O—, and preferably L is a bond or C1-C6 alkylene, wherein one or two —CH2— units comprised in said alkylene are each optionally replaced by —O—, and further wherein R is selected from hydrogen, optionally substituted phenyl, optionally substituted heteroaryl having 5 or 6 ring atoms, wherein 1, 2, or 3 ring atoms are each independently selected from O, S, or N and the other ring atoms are carbon atoms; or optionally substituted heterocycloalkyl having 5 to 7 ring atoms, wherein one or two ring atoms are each independently selected from N or O and the other ring atoms are carbon atoms. Said optionally substituted phenyl, said optionally substituted heteroaryl having 5 or 6 ring atoms, or said optionally substituted heterocycloalkyl having 5 to 7 ring atoms may be substituted with one or more, preferably one or two, groups independently selected from C1-C4 alkyl, —(C1-C4 alkylene)-OH, —(C1-C4 alkylene)-O—(C1-C4 alkyl), —OH, —O(C1-C4 alkyl), —O—(C1-C4 alkylene)-O—(C1-C4 alkyl), —NH2, —NH(C1-C4 alkyl), or —N(C1-C4 alkyl)(C1-C4 alkyl) wherein the two C1-C4 alkyl moieties of said —N(C1-C4 alkyl)(C1-C4 alkyl) are optionally mutually linked to form a ring together with the nitrogen atom which they are attached to, —CF3, or halogen, and more preferably selected from C1-C4 alkyl, —(C1-C4 alkylene)-OH, —(C1-C4 alkylene)-O—(C1-C4 alkyl), —O(C1-C4 alkyl), —N(C1-C4 alkyl)(C1-C4 alkyl) wherein the two C1-C4 alkyl moieties of said —N(C1-C4 alkyl)(C1-C4 alkyl) are optionally mutually linked to form a ring together with the nitrogen atom which they are attached to, or halogen.

Exemplary preferred -L-R groups encompassed by the above preferred definition are independently selected from: hydrogen; C1-C4 alkyl; —(C1-C3 alkylene)-O—(C1-C2 alkyl); —(C2-C4 alkynylene)-phenyl; —OH; —O(C1-C4 alkyl); —O(C1-C2 alkylene)-O—(C1-C2 alkyl); —(C1-C4 alkylene)-morpholinyl; —O(C1-C4 alkylene)-phenyl; —O(C1-C4 alkylene)-imidazolyl; —O(C1-C4 alkylene)-pyrrolidinyl; —O(C1-C4 alkylene)-piperidinyl; —O(C1-C4 alkylene)-morpholinyl; —O(C1-C4 alkylene)-pyridinyl; —O(C1-C4 alkylene)-oxazepanyl; —O(C1-C4 alkylene)-(2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl); —O(C1-C4 alkylene)-piperazinylene-(C1-C4 alkyl); or —O(C1-C4 alkylene)-diazepanylene-(C1-C4 alkyl); wherein the phenyl, imidazolyl, pyrrolidinyl, piperidinyl, morpholinyl, pyridinyl, oxazepanyl, 2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl, piperazinylene, and diazepanylene moieties are each optionally substituted with one or more, preferably one or two, groups independently selected from halogen, —CF3, C1-C4 alkyl, —(C1-C4 alkylene)-OH, —(C1-C4 alkylene)-O—(C1-C4 alkyl), —OH, —O(C1-C4 alkyl), —O—(C1-C4 alkylene)-O—(C1-C4 alkyl), —NH2, —NH(C1-C4 alkyl), or —N(C1-C4 alkyl)(C1-C4 alkyl) wherein the two C1-C4 alkyl moieties of said —N(C1-C4 alkyl)(C1-C4 alkyl) are optionally mutually linked to form a ring together with the nitrogen atom which they are attached to, more preferably selected from halogen, C1-C4 alkyl, —(C1-C4 alkylene)-OH, —(C1-C4 alkylene)-O—(C1-C4 alkyl), —O(C1-C4 alkyl), or —N(C1-C4 alkyl)(C1-C4 alkyl) wherein the two C1-C4 alkyl moieties of said —N(C1-C4 alkyl)(C1-C4 alkyl) are optionally mutually linked to form a ring together with the nitrogen atom which they are attached to.

Moreover, in particularly preferred embodiments, either R1 to R4 are all hydrogen, or one of R1 to R4 is a -L-R group other than hydrogen as defined above and the other ones of R1 to R4 are hydrogen. In this latter preferred embodiment, the -L-R group other than hydrogen is in particular one of R2 and R3, and more preferably R2.

Accordingly, in one preferred embodiment R1 and R4 are each hydrogen, one of R2 and R3 (preferably R3) is hydrogen, and the other one of R2 and R3 (preferably R2) is selected from: hydrogen; C1-C4 alkyl; —(C1-C3 alkylene)-O—(C1-C2 alkyl); —(C2-C4 alkynylene)-phenyl; —OH; —O(C1-C4 alkyl); —O(C1-C2 alkylene)-O—(C1-C2 alkyl); —(C1-C4 alkylene)-morpholinyl; —O(C1-C4 alkylene)-phenyl; —O(C1-C4 alkylene)-imidazolyl; —O(C1-C4 alkylene)-pyrrolidinyl; —O(C1-C4 alkylene)-piperidinyl; —O(C1-C4 alkylene)-morpholinyl; —O(C1-C4 alkylene)-pyridinyl; —O(C1-C4 alkylene)-oxazepanyl; —O(C1-C4 alkylene)-(2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl); —O(C1-C4 alkylene)-piperazinylene-(C1-C4 alkyl); or —O(C1-C4 alkylene)-diazepanylene-(C1-C4 alkyl); wherein the phenyl, imidazolyl, pyrrolidinyl, piperidinyl, morpholinyl, pyridinyl, oxazepanyl, 2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl, piperazinylene, and diazepanylene moieties are each optionally substituted with one or more, preferably one or two, groups independently selected from halogen, —CF3, C1-C4 alkyl, —(C1-C4 alkylene)-OH, —(C1-C4 alkylene)-O—(C1-C4 alkyl), —OH, —O(C1-C4 alkyl), —O—(C1-C4 alkylene)-O—(C1-C4 alkyl), —NH2, —NH(C1-C4 alkyl), or —N(C1-C4 alkyl)(C1-C4 alkyl) wherein the two C1-C4 alkyl moieties of said —N(C1-C4 alkyl)(C1-C4 alkyl) are optionally mutually linked to form a ring together with the nitrogen atom which they are attached to, more preferably selected from halogen, C1-C4 alkyl, —(C1-C4 alkylene)-OH, —(C1-C4 alkylene)-O—(C1-C4 alkyl), —O(C1-C4 alkyl), or —N(C1-C4 alkyl)(C1-C4 alkyl) wherein the two C1-C4 alkyl moieties of said —N(C1-C4 alkyl)(C1-C4 alkyl) are optionally mutually linked to form a ring together with the nitrogen atom which they are attached to. In one aspect of this embodiment, one of R2 and R3 (preferably R3) is hydrogen, and the other one of R2 and R3 (preferably R2) is not hydrogen.

R11 and R12 are each independently selected from hydrogen, optionally substituted C1-C10 alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, or —CF3, wherein said optionally substituted alkyl, said optionally substituted aryl, said optionally substituted heteroaryl, said optionally substituted cycloalkyl, or said optionally substituted heterocycloalkyl may be substituted with one or more, preferably one or two, more preferably one, groups independently selected from C1-C4 alkyl, halogen, —CF3, —CN, —OH, —O(C1-C4 alkyl), —NH2, —NH(C1-C4 alkyl), or —N(C1-C4 alkyl)(C1-C4 alkyl) wherein the two C1-C4 alkyl moieties of said —N(C1-C4 alkyl)(C1-C4 alkyl) are optionally mutually linked to form a ring (such as, e.g., a pyrrolidinyl ring or a piperidinyl ring) together with the nitrogen atom which they are attached to. It is preferred that the aforementioned groups are unsubstituted. Preferably, R11 and R12 are each independently selected from hydrogen, or C1-C4 alkyl.

L1 is selected from a bond, C1-C10 alkylene, C2-C10 alkenylene, or C2-C10 alkynylene, wherein one or two —CH2— units comprised in said alkylene, said alkenylene or said alkynylene are each optionally replaced by a group independently selected from —O—, —NH—, —N(C1-C4 alkyl)-, —CO—, —S—, —SO— or —SO2—. This includes the option that the replacing group —NH— or the replacing group —N(C1-C4 alkyl)- is combined with the replacing group —CO—, in any order, to form an amide group. Otherwise, if more than one —CH2— unit is replaced, it is preferred that these —CH2— units are non-adjacent.

Preferably, L1 is selected from a bond, C1-C6 alkylene, C2-C6 alkenylene, or C2-C6 alkynylene, wherein one or two —CH2— units comprised in said alkylene, said alkenylene or said alkynylene are each optionally replaced by a group independently selected from —O—, —NH—, —CO—, or —S—.

More preferably, L1 is selected from a bond, C1-C6 alkylene, C2-C6 alkenylene, or C2-C6 alkynylene, wherein one or two —CH2— units comprised in said alkylene, said alkenylene or said alkynylene are each optionally replaced by a group independently selected from —O—, —NH—, or —S—.

Even more preferably, L1 is a bond, C1-C6 alkylene, C2-C6 alkenylene, or C2-C6 alkynylene, wherein one or two —CH2— units comprised in said alkylene, said alkenylene or said alkynylene are each optionally replaced by —O—.

Most preferably, L1 is a bond or C1-C6 alkylene, wherein one or two —CH2— units comprised in said alkylene are each optionally replaced by —O—.

R13 is selected from hydrogen, C1-C4 alkyl, halogen, optionally substituted phenyl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, —NH2, —NH(C1-C4 alkyl), —N(C1-C4 alkyl)(C1-C4 alkyl), —OH, —O(C1-C4 alkyl), —SH, —S(C1-C4 alkyl), —CF3, or —CN, wherein said optionally substituted phenyl, said optionally substituted heteroaryl, said optionally substituted cycloalkyl, or said optionally substituted heterocycloalkyl may be substituted with one or more, preferably one or two, more preferably one, groups independently selected from C1-C4 alkyl, halogen, —CF3, —CN, —OH, —O(C1-C4 alkyl), —NH2, —NH(C1-C4 alkyl), or —N(C1-C4 alkyl)(C1-C4 alkyl) wherein the two C1-C4 alkyl moieties of said —N(C1-C4 alkyl)(C1-C4 alkyl) are optionally mutually linked to form a ring (such as, e.g., a pyrrolidinyl ring or a piperidinyl ring) together with the nitrogen atom which they are attached to.

Preferably, R13 is selected from hydrogen, C1-C4 alkyl, halogen, optionally substituted phenyl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, —NH(C1-C4 alkyl), —N(C1-C4 alkyl)(C1-C4alkyl), —O(C1-C4 alkyl), —S(C1-C4 alkyl), —CF3, or —CN.

More preferably, R13 is selected from: hydrogen; C1-C4 alkyl; halogen; optionally substituted phenyl; optionally substituted heteroaryl having 5 or 6 ring atoms, wherein 1, 2, or 3 ring atoms are each independently selected from O, S, or N and the other ring atoms are carbon atoms; cycloalkyl having 3 to 7 ring atoms; optionally substituted heterocycloalkyl having 3 to 10 ring atoms, wherein one or more (such as, e.g., one, two, or three) ring atoms are each independently selected from O, S, or N and the other ring atoms are carbon atoms; —NH(C1-C4 alkyl); —N(C1-C4 alkyl)(C1-C4 alkyl); —O(C1-C4 alkyl); —S(C1-C4 alkyl); —CF3; or —CN.

Even more preferably, R13 is selected from: hydrogen; —O(C1-C4 alkyl); optionally substituted phenyl; optionally substituted heteroaryl having 5 or 6 ring atoms, wherein 1, 2, or 3 ring atoms are each independently selected from O, S, or N and the other ring atoms are carbon atoms; or optionally substituted heterocycloalkyl having 3 to 10 ring atoms, wherein one or more ring atoms are each independently selected from O, S, or N and the other ring atoms are carbon atoms.

R5 is selected from hydrogen, C1-C4 alkyl, halogen, —CF3, —CN, —OH, —O(C1-C4 alkyl), —COOH, —COO(C1-C4 alkyl), —CONH2, —CONH(C1-C4 alkyl), —CON(C1-C4 alkyl)(C1-C4 alkyl) wherein the two C1-C4 alkyl moieties of said —CON(C1-C4 alkyl)(C1-C4 alkyl) are optionally mutually linked to form a ring (such as, e.g., a pyrrolidinyl ring or a piperidinyl ring) together with the nitrogen atom which they are attached to, —NH2, —NH(C1-C4 alkyl), or —N(C1-C4 alkyl)(C1-C4 alkyl) wherein the two C1-C4 alkyl moieties of said —N(C1-C4 alkyl)(C1-C4 alkyl) are optionally mutually linked to form a ring (such as, e.g., a pyrrolidinyl ring or a piperidinyl ring) together with the nitrogen atom which they are attached to. Said halogen may, for example, be selected from fluoro, chloro, bromo, or iodo. Preferably, R5 is selected from hydrogen, C1-C4 alkyl, halogen, —CF3, —CN, —OH, or —O(C1-C4 alkyl). More preferably, R5 is selected from hydrogen or C1-C4 alkyl. Even more preferably, R5 is hydrogen.

A is a bicyclic moiety corresponding to formula (II):

which may be saturated or unsaturated, i.e. one or more double bonds may be present in one or both rings formed by X1 to X9. This includes the option that one or both rings formed by X1 to X9 are aromatic.

n is 0 or 1.

X1 to X6 are each independently selected from N,N(Rx1), C(Rx2), C(Rx2)(Rx3), O, S, S(O), S(O)2, or C(O). Preferably, X1 to X6 are each independently selected from N, N(Rx1), C(Rx2), C(Rx2)(Rx3), S or O.

X7 is N or N(Rx1).

Included is furthermore the option that any of groups X1 to X7 containing a nitrogen atom can form an N-oxide group.

X8 and X9 are each independently selected from N, C, or C(Rx2).

Each Rx1 is independently selected from hydrogen, C1-C4 alkyl, —OH, —O(C1-C4 alkyl), or —(C1-C4 alkylene)-phenyl. Preferably, each Rx1 is independently selected from hydrogen, or C1-C4 alkyl.

Each Rx2 and each Rx3 is independently selected from hydrogen, C1-C4 alkyl, halogen, —CF3, —CN, —OH, —O(C1-C4 alkyl), —COOH, —COO(C1-C4 alkyl), —CONH2, —CONH(C1-C4 alkyl), —CON(C1-C4 alkyl)(C1-C4 alkyl), —NH2, —NH(C1-C4 alkyl), or —N(C1-C4 alkyl)(C1-C4 alkyl), wherein the two C1-C4 alkyl moieties of said —N(C1-C4 alkyl)(C1-C4 alkyl) or of said —CON(C1-C4 alkyl)(C1-C4 alkyl) are optionally mutually linked to form a ring (such as, e.g., a pyrrolidinyl ring or a piperidinyl ring) together with the nitrogen atom which they are attached to. Preferably, each Rx2 and each Rx3 is independently selected from hydrogen, C1-C4 alkyl, halogen, —CF3, —CN, —OH, —O(C1-C4 alkyl), —NH2, —NH(C1-C4 alkyl), or —N(C1-C4 alkyl)(C1-C4 alkyl) wherein the two C1-C4 alkyl moieties of said —N(C1-C4 alkyl)(C1-C4 alkyl) are optionally mutually linked to form a ring together with the nitrogen atom which they are attached to. More preferably, each Rx2 and each Rx3 is independently selected from hydrogen, C1-C4 alkyl, halogen, —CF3, —OH, or —O(C1-C4 alkyl).

. As will further be understood, the absence or the presence of one or two substituents Rx1, Rx2 and Rx3 in the groups X1 to X9 will depend on the presence and the position of double bonds in the bicyclic ring system of formula (II).

In preferred embodiments, one or two of the groups X1 to X6, X8 and X9 are each independently selected from N, N(Rx1), O, S, S(O), or S(O)2 (preferably, selected from N,N(Rx1), S or O) in the case of X1 to X6 and from N in the case of X8 and X9, respectively, and the remaining groups X1 to X6, X8 and X9 are each independently selected from C(Rx2) or C(Rx2)(Rx3) in the case of X1 to X6 and from C or C(Rx2) in the case of X8 and X9, respectively. Accordingly, in one embodiment one or two of the groups X1 to X6 are each independently selected from N,N(Rx1), O, or S, the remaining groups X1 to X6 are each independently selected from C(Rx2) or C(Rx2)(Rx3), and X8 and X9 are each independently selected from C or C(Rx2); alternatively, in another embodiment one or none of the groups X1 to X6 is selected from N,N(Rx1), O, or S, the remaining groups X1 to X6 are each independently selected from C(Rx2) or C(Rx2)(Rx3), one of X8 and X9 is N, and the other one of X8 and X9 is C or C(Rx2).

In further preferred embodiments, one or two of the groups X1 to X6, X8 and X9 are each independently selected from N,N(Rx1) or S in the case of X1 to X6 and from N in the case of X8 and X9, respectively, and the remaining groups X1 to X6, X8 and X9 are each independently selected from C(Rx2) or C(Rx2)(Rx3) in the case of X1 to X6 and from C or C(Rx2) in the case of X8 and X9, respectively. Accordingly, in one embodiment one or two of X1 to X6 are each independently selected from N,N(Rx1) or S, the remaining groups X1 to X6 are each independently selected from C(Rx2) or C(Rx2)(Rx3), and X8 and X9 are each independently selected from C or C(Rx2); alternatively, in another embodiment one or none of the groups X1 to X6 is selected from N,N(Rx1) or S, the remaining groups X1 to X6 are each independently selected from C(Rx2) or C(Rx2)(Rx3), one of X8 and X9 is N, and the other one of X8 and X9 is C or C(Rx2).

It is preferred that A is a bicyclic moiety corresponding to formula (II) as described and defined herein above, wherein the first ring of the bicyclic moiety (i.e. the ring which is linked to the remainder of the compound of general formula (I)) is aromatic, and it is more preferred that A is a bicyclic moiety corresponding to formula (II) as described and defined herein above, wherein the two rings of the bicyclic moiety form an aromatic ring system.

It is particularly preferred that A is one of the following groups:

each of which may optionally be substituted on ring carbon atoms with one or more groups independently selected from C1-C4 alkyl, halogen, —CF3, —CN, —OH, —O(C1-C4 alkyl), —NH2, —NH(C1-C4 alkyl), or —N(C1-C4 alkyl)(C1-C4 alkyl) wherein the two C1-C4 alkyl moieties of said —N(C1-C4 alkyl)(C1-C4 alkyl) are optionally mutually linked to form a ring together with the nitrogen atom which they are attached to, and preferably selected from C1-C4 alkyl, halogen, —OH, or —O(C1-C4 alkyl). Furthermore, each Rx1 (if present) is independently selected from hydrogen, C1-C4 alkyl, —OH, or —O(C1-C4 alkyl), and preferably selected from hydrogen or C1-C4 alkyl. Each Rx4 (if present) is independently selected from hydrogen or C1-C4 alkyl, or the two groups Rx4 (if present) are each independently C1-C4 alkyl and are mutually linked to form a ring (such as, e.g., a pyrrolidinyl ring or a piperidinyl ring) together with the nitrogen atom which they are attached to. It is preferred that the above depicted optionally substituted groups are unsubstituted and Rx1 (if present) is hydrogen.

More preferably, A is one of the following groups:

each of which may optionally be substituted on ring carbon atoms with one or more groups independently selected from C1-C4 alkyl, halogen, —CF3, —CN, —OH, —O(C1-C4 alkyl), —NH2, —NH(C1-C4 alkyl), or —N(C1-C4 alkyl)(C1-C4 alkyl) wherein the two C1-C4 alkyl moieties of said —N(C1-C4 alkyl)(C1-C4 alkyl) are optionally mutually linked to form a ring together with the nitrogen atom which they are attached to, and preferably selected from C1-C4 alkyl, halogen, —OH, or —O(C1-C4 alkyl). It is preferred that the above depicted optionally substituted groups are unsubstituted.

Even more preferably, A is one of the following groups:

each of which may optionally be substituted on ring carbon atoms with one or more groups independently selected from C1-C4 alkyl, halogen, —CF3, —CN, —OH, —O(C1-C4 alkyl), —NH2, —NH(C1-C4 alkyl), or —N(C1-C4 alkyl)(C1-C4 alkyl) wherein the two C1-C4 alkyl moieties of said —N(C1-C4 alkyl)(C1-C4 alkyl) are optionally mutually linked to form a ring together with the nitrogen atom which they are attached to, and preferably selected from C1-C4 alkyl, halogen, —OH, or —O(C1-C4 alkyl). It is preferred that the above depicted optionally substituted groups are unsubstituted.

It is particularly preferred that the compound of the general formula (I) is selected from: 2-isoquinolin-3-yl-chromen-4-one oxime; 7-bromo-2-isoquinolin-3-yl-chromen-4-one oxime; 7-bromo-2-isoquinolin-3-yl-6-methyl-chromen-4-one oxime; 6-bromo-2-isoquinolin-3-yl-chromen-4-one oxime; 2-isoquinolin-3-yl-6-methyl-chromen-4-one oxime; 6-fluoro-2-isoquinolin-3-yl-chromen-4-one oxime; 6,8-diffluoro-2-isoquinolin-3-yl-chromen-4-one oxime; 8-chloro-2-isoquinolin-3-yl-chromen-4-one oxime; 4-fluoro-2-isoquinolin-3-yl-chromen-4-one-(Z)-oxime; 2-isoquinolin-3-yl-6-trifluoromethoxy-chromen-4-one oxime; 2-isoquinolin-3-yl-6-trifluoromethyl-chromen-4-one oxime; 2-(7-fluoro-isoquinolin-3-yl)-chromen-4-one oxime; 2-(7-methoxy-isoquinolin-3-yl)-chromen-4-one oxime; 2-(6,7-dimethoxy-isoquinolin-3-yl)-chromen-4-one oxime; 2-(6-methyl-isoquinolin-3-yl)-chromen-4-one oxime; 2-(7-chloro-isoquinolin-3-yl)-chromen-4-one oxime; 2-(5-bromo-isoquinolin-3-yl)-chromen-4-one oxime; 2-(5-hydroxy-isoquinolin-3-yl)-chromen-4-one oxime; 2-(5-methoxy-isoquinolin-3-yl)-chromen-4-one oxime; 2-isoquinolin-3-yl-7-phenylethynyl-chromen-4-one oxime; 2-isoquinolin-3-yl-7-((E)-styryl)-chromen-4-one oxime; 2-isoquinolin-3-yl-7-phenethyl-chromen-4-one oxime; 7-ethynyl-2-isoquinolin-3-yl-chromen-4-one oxime; 2-isoquinolin-3-yl-7-(pyridin-2-yl-ethynyl)-chromen-4-one oxime; 2-isoquinolin-3-yl-7-(pyridin-2-yl-ethynyl)-chromen-4-one oxime; 2-isoquinolin-3-yl-7-(pyridin-4-yl)ethynyl-chromen-4-one oxime; 7-(4-dimethylaminophenyl)ethynyl-2-isoquinolin-3-yl-chromen-4-one oxime; 2-isoquinolin-3-yl-7-(3-methoxyphenyl)ethynyl-chromen-4-one oxime; 7-(3-aminophenyl)ethynyl-2-isoquinolin-3-yl-chromen-4-one oxime; 7-(3-hydroxyphenyl)ethynyl-2-isoquinolin-3-yl-chromen-4-one oxime; 2-isoquinolin-3-yl-7-(4-methoxyphenyl)ethynyl-chromen-4-one oxime; 7-(2-chlorophenyl)ethynyl-2-isoquinolin-3-yl-chromen-4-one oxime; 7-(3-dimethylamino-prop-1-ynyl)-2-isoquinolin-3-yl-chromen-4-one oxime; 6-cyclopropyl-2-isoquinolin-3-yl-chromen-4-one oxime; 2-isoquinolin-3-yl-6-(pyrrolidin-1-yl)-chromen-4-one oxime; 2-isoquinolin-3-yl-6-(vinyl)-chromen-4-one oxime; 6-ethyl-2-isoquinolin-3-yl-chromen-4-one oxime; 6-cyano-2-isoquinolin-3-yl-chromen-4-one oxime; 6-dimethylamino-2-isoquinolin-3-yl-chromen-4-one oxime; 2-isoquinolin-3-yl-6-(morpholin-4-yl-methyl)-chromen-4-one oxime; 6-hydroxy-2-isoquinolin-3-yl-chromen-4-one oxime; 2-isoquinolin-3-yl-6-methoxy-chromen-4-one oxime; 2-isoquinolin-3-yl-6-(2-methoxy-ethoxy)-chromen-4-one oxime; 6-(2-dimethylamino-ethoxy)-2-isoquinolin-3-yl-chromen-4-one oxime; 2-isoquinolin-3-yl-6-[3-(4-methyl-piperazin-1-yl)-propylamino]-chromen-4-one oxime; 2-isoquinolin-3-yl-6-[2-(4-methyl-piperazin-1-yl)-ethoxy]-chromen-4-one oxime; 2-isoquinolin-3-yl-7-phenyl-chromen-4-one oxime; 7-(4-biphenyl)-2-isoquinolin-3-yl-chromen-4-one oxime; 2-isoquinolin-3-yl-7-[3-(4-methyl-piperazin-1-yl)-propylamino]-chromen-4-one oxime; 2-Isoquinolin-3-yl-7-{3-[2-(4-methyl-piperazin-1-yl)-ethoxy]-phenylethynyl}-chromen-4-one oxime; 2-Isoquinolin-3-yl-7-{3-methylaminophenylethynyl}-chromen-4-one oxime; 7-(4-Hydroxy-but-1-ynyl)-2-isoquinolin-3-yl-chromen-4-one oxime; 2-Isoquinolin-3-yl-7-{3-(2-methoxy-ethoxy)-phenylethynyl}-chromen-4-one oxime; 2-Isoquinolin-3-yl-7-[3-(2-methoxy-ethoxy)-prop-1-ynyl]-chromen-4-one oxime; 7-but-3-en-1-ynyl-2-Isoquinolin-3-yl-chromen-4-one oxime; 2-isoquinolin-3-yl-7-methoxy-chromen-4-one oxime; 2-isoquinolin-3-yl-7-(2-methoxy-ethoxy)-chromen-4-one oxime; 7-cyano-2-isoquinolin-3-yl-chromen-4-one oxime; 2-Isoquinolin-3-yl-7-[3-(4-methyl-piperazin-1-yl)-prop-1-ynyl]-chromen-4-one oxime; 2-(7-hydroxy-isoquinolin-3-yl)-chromen-4-one oxime; 2-[2,6]Naphthyndin-3-yl-chromen-4-one oxime; 2-[1,6]Naphthyridin-3-yl-chromen-4-one oxime; 2-Pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one oxime; 2-(5,7-dimethyl-Pyrrolo[1,2-c]pyrimidin-3-yl)-chromen-4-one oxime; 2-(6-bromo-Pyrrolo[1,2-o]pyrimidin-3-yl)-chromen-4-one oxime; 6-bromo-2-Pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one oxime; 6-methoxyethoxy-2-Pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one oxime; 2-(1-Benzyl-1H-imidazo[4,5-c]pyridin-6-yl)-chromen-4-one oxime; 2-Thieno[2,3-c]pyridin-5-yl-chromen-4-one oxime; 2-Thieno[3,2-c]pyridin-6-yl-chromen-4-one oxime; 2-Isoquinolin-3-yl-3-methyl-chromen-4-one oxime; 3-{4-[(E)-Hydroxyimino]-4H-1-chromen-2-yl}-2H-isoquinolin-1-one; 2-Imidazo[1,2-c]pyrimidin-7-yl-chromen-4-one oxime; 2-(1H-Pyrrolo[2,3-c]pyridin-5-yl)-chromen-4-one oxime; 2-(1-Hydroxy-1H-pyrrolo[2,3-c]pyridin-5-yl)-chromen-4-one oxime; 2-(1-Methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)-chromen-4-one oxime; 2-(1-Methoxy-1H-pyrrolo[2,3-c]pyridin-5-yl)-chromen-4-one oxime; 6-Hydroxy-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one oxime; 2-Thiazolo[5,4-c]pyridin-6-yl-chromen-4-one oxime; 6-(3-Methoxy-propyl)-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one oxime; 6-(3-Dimethylamino-propoxy)-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one oxime; 6-(3-Morpholin-4-yl-ethoxy)-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one oxime; 6-(2,3-Dihydroxy-propoxy)-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one oxime; 6-(2-Pyrrolidin-1-yl-ethoxy)-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one oxime; 6-(2-Piperidin-1-yl-ethoxy)-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one oxime; 6-(2-dimethylamino-ethoxy)-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one oxime; 6-(2-diethylamino-ethoxy)-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one oxime; 2-Pyrrolo[1,2-a]pyrazin-3-yl-chromen-4-one oxime; 6-[2-(2-methyl-pyrrolidin-1-yl)-ethoxy]-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one oxime; 6-[2-(4-methyl-piperazin-1-yl)-ethoxy]-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one oxime; 6-[2-(4-methyl-[1,4]diazepan-1-yl)-ethoxy]-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one oxime; 6-[2-((S)-2-hydroxymethylpyrroridin-1-yl)-ethoxy]-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one oxime; 6-[2-((S)-2-methoxymethylpyrrolidin-1-yl)-ethoxy]-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one oxime; 6-[2-((R)-2-methoxymethylpyrrolidin-1-yl)-ethoxy]-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one oxime; 6-[2-(3-hydroxy-pyrrolidin-1-yl)-ethoxy]-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one oxime; 6-[2-(4-dimethylamino-piperidin-1-yl)-ethoxy]-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one oxime; 6-(2-cyclopentylamino-ethoxy)-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one oxime; 6-(3-morpholin-4-yl-propoxy)-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one oxime; 6-(4-morpholin-4-yl-butyl)-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one oxime; 6-(4,4-difluoro-piperidin-1-yl)-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one oxime; 6-{2-[bis-(2-methoxy-ethyl)-amino]-ethoxy}-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one oxime; 6-(2-Imidazol-1-yl-ethoxy)-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one oxime; 6-(3-morpholin-4-yl-propyl)-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one oxime; 6-((Z)-3-Morpholin-4-yl-propenyl))-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one oxime; 6-[2-(3-methoxy-piperidin-1-yl)-ethoxy]-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one oxime; 6-[2-(4-fluoro-phenyl)-ethoxy]-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one oxime; 2-quinazolin-2-yl-chromen-4-one oxime; 6-[(1S,4S)-2-(2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl)-ethoxy]-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one oxime; 6-[2-(cis-2,6-dimethyl-morpholin-4-yl)-ethoxy]-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one oxime; 2-pyrrolo[1,2-c]pyrimidin-3-yl-6-[2-(4-trifluoromethyl-piperidin-1-yl)-ethoxy]-chromen-4-one oxime; 6-[2-(3,3-difluoro-piperidin-1-yl)-ethoxy]-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one oxime; 4-(hydroxyimino)-2-pyrrolo[1,2-c]pyrimidin-3-yl-4H-chromene-6-carboxylic acid (2-morpholin-4-yl-ethyl)-amide; 6-(2-[1,4′]bipiperidinyl-1′-yl-ethoxy)-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one oxime; 6-(2-[1,4]oxazepan-4-yl-ethoxy)-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one oxime; 6-[2-(4-pyrrolidin-1-yl-piperidin-1-yl)-ethoxy]-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one oxime; 6-[2-(3,3-difluoro-pyrrolidin-1-yl)-ethoxy]-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one oxime; 7-[3-(3-dimethylamino-propoxy)-phenylethynyl]-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one oxime; 6-[2-(4-ethyl-piperazin-1-yl)-ethoxy]-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one oxime; 6-(2-amino-ethoxy)-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one oxime; 6-(2-Morpholin-4-yl-ethoxy)-2-(8aH-pyrrolo[1,2-a]pyrazin-3-yl)-chromen-4-one oxime; 6-[2-(4,4-Difluoro-piperidin-1-yl)-ethoxy]-2-pyrrolo[1,2-a]pyrazin-3-yl-chromen-4-one oxime; 6-(2-Imidazol-1-yl-ethoxy)-2-pyrrolo[1,2-a]pyrazin-3-yl-chromen-4-one oxime; 6-[2-(4-Fluoro-phenyl)-ethoxy]-2-pyrrolo[1,2-a]pyrazin-3-yl-chromen-4-one oxime; 6-(2-Morpholin-4-yl-ethoxy)-2-thieno[3,2-c]pyridin-6-yl-chromen-4-one oxime;

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